Vuong Wayne, Khan Muhammad Bashir, Fischer Conrad, Arutyunova Elena, Lamer Tess, Shields Justin, Saffran Holly A, McKay Ryan T, van Belkum Marco J, Joyce Michael A, Young Howard S, Tyrrell D Lorne, Vederas John C, Lemieux M Joanne
Department of Chemistry, University of Alberta, Edmonton, T6G 2G2, AB, Canada.
Department of Biochemistry, Membrane Protein Disease Research Group, University of Alberta, Edmonton, T6G 2R3, AB, Canada.
Nat Commun. 2020 Aug 27;11(1):4282. doi: 10.1038/s41467-020-18096-2.
The main protease, M (or 3CL) in SARS-CoV-2 is a viable drug target because of its essential role in the cleavage of the virus polypeptide. Feline infectious peritonitis, a fatal coronavirus infection in cats, was successfully treated previously with a prodrug GC376, a dipeptide-based protease inhibitor. Here, we show the prodrug and its parent GC373, are effective inhibitors of the M from both SARS-CoV and SARS-CoV-2 with IC values in the nanomolar range. Crystal structures of SARS-CoV-2 M with these inhibitors have a covalent modification of the nucleophilic Cys145. NMR analysis reveals that inhibition proceeds via reversible formation of a hemithioacetal. GC373 and GC376 are potent inhibitors of SARS-CoV-2 replication in cell culture. They are strong drug candidates for the treatment of human coronavirus infections because they have already been successful in animals. The work here lays the framework for their use in human trials for the treatment of COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）的主要蛋白酶M（或3CL）是一个可行的药物靶点，因为它在病毒多肽切割中起着关键作用。猫传染性腹膜炎是猫的一种致命冠状病毒感染，此前用前药GC376（一种基于二肽的蛋白酶抑制剂）成功进行了治疗。在此，我们表明该前药及其母体GC373是严重急性呼吸综合征冠状病毒（SARS-CoV）和SARS-CoV-2的M的有效抑制剂，其半数抑制浓度（IC）值在纳摩尔范围内。这些抑制剂与SARS-CoV-2 M的晶体结构显示亲核性半胱氨酸145发生了共价修饰。核磁共振分析表明抑制作用是通过半硫代缩醛的可逆形成来进行的。GC373和GC376在细胞培养中是SARS-CoV-2复制的有效抑制剂。它们是治疗人类冠状病毒感染的有力候选药物，因为它们在动物实验中已经取得成功。本文的工作为它们用于治疗2019冠状病毒病（COVID-19）的人体试验奠定了基础。
